More than 500 million people worldwide (10% of the adult population) have some form of kidney damage, and every year millions die prematurely of cardiovascular diseases linked to chronic kidney disease. Diabetes mellitus (DM) is the most common and rapidly growing cause of end-stage renal disease in developed countries. The incidence of diabetes mellitus and obesity are rapidly rising to epidemic levels in the United States and worldwide. Hyperglycemia, the metabolic hallmark of the pathology is a significant causative factor for the complications of diabetes mellitus, which results in significant morbidity and mortality for millions of Americans.
Renin-angiotensin system (RAS) activation in diabetes mellitus and the metabolic syndrome is a core abnormality that leads to many complications of the disease, including hypertension, proteinuria, and renal tissue injury (1, 2). It has been difficult to isolate acute and direct actions of hyperglycemia on glomerular structures from the systemic factors and complex intrarenal feedback mechanisms (3) that can indirectly activate the RAS. Therefore, the primary cause and exact mechanism of RAS activation in early diabetes is still elusive.
The G protein-coupled receptor, GPR91, which functions as a detector of cell metabolism (4, 5), may provide a new, direct link between hyperglycemia and RAS activation. Its ligand, the TCA cycle intermediate succinate (4), which is normally present in the mitochondria, can be released extracellularly if the local tissue energy supply and demand is out of balance (5). Succinate accumulation caused by restricted organ blood supply (local ischemia), GPR91 activation, and subsequent renin release has been recently implicated in the development of renovascular hypertension (4). GPR91 is present in many organs, including the kidney, liver, spleen, breast, and blood vessels, but it is expressed most abundantly in the kidney (4, 6). In the renal cortex, GPR91 was detected in various nephron segments and in the juxtaglomerular apparatus (JGA) (4), although the specific cellular localization has not been determined.
The JGA represents the major structural component of the RAS and is one of the most important regulatory sites of systemic blood pressure (7-9). Renin-producing juxtaglomerular (JG) cells, located in the wall of the terminal afferent arteriole, are key components of the JGA and receive numerous chemical signals from adjacent vascular endothelial, smooth muscle, and tubular epithelial cells that precisely control the rate of renin release (8). Classic chemical mediators that stimulate renin release include prostaglandins (PGE2 and PGI2) and NO (8, 9). Release of renin from JG cells is considered the rate-limiting step of RAS activation, and it ultimately leads to the generation of Ang II, the main RAS product and the primary effector of pathology in diabetes (1). In addition, the renin precursor prorenin, which is also produced and released by JG cells, has been directly implicated in diabetic nephropathy (10).
Succinate has been shown to cause the release of the hypertensive hormone renin from the kidney (11). Consistent with the key role of succinate as a signaling molecule for GPR91 activation, and its involvement in the pathogenesis of hypertension and metabolic diseases, the accumulation of succinate in plasma samples was recently reported (21). However, this was observed only in rodent models and not in humans (21). At the same time, our laboratory demonstrated local accumulation of succinate in the diabetic kidney tissue to levels that are consistent with GPR91 activation (13). We measured succinate in non-diabetic and diabetic kidney tissue and urine samples. In freshly harvested urine and whole kidney tissue samples of non-diabetic mice the succinate concentration was 26±7 and 10±0.2 μM, respectively. In contrast, 1-2 orders of magnitude higher levels were detected in samples from diabetic animals (168±45 μM in urine, 616±62 μM in tissue). This new finding indicates that urinary succinate rather than plasma succinate should be measured as a sign of kidney tissue damage. Our data are consistent with the local accumulation of succinate in the damaged kidney tissue which is reflected in urinary succinate levels (13). In addition to rodent tissue and urine, we now have supporting data using human urine samples that urinary succinate is a potential biomarker and an early predictor of kidney disease in humans. In a recent, unpublished clinical study consisting of 90 patients we found that succinate content of spot human urine samples (using the succinate/creatinin ratio which is independent of urinary concentration/dilution) was increased 4-fold in diabetic patients with chronic kidney disease (FIG. 9). This further suggests the importance of the succinate-GPR91 signaling pathway in kidney disease as well as the utility of this novel biomarker, similar to the mechanism described in rodent kidneys. Succinate is not only the direct cause of pathology, but urinary succinate can be used as an ideal biomarker of kidney tissue damage. and an early predictor of pathology. Because of the newly discovered GPR91 receptor and its role in RAS activation (4), we believe that it is a (patho)physiologically significant mediator by which high levels of glucose supply and metabolism at the onset of diabetes directly cause renin release through succinate and GPR91 signaling in the JGA.